Thrombin is a well characterized member of the serine protease family which is involved in the final steps of the blood coagulation pathway. Relative to the other members of the serine protease class of enzymes, thrombin has an unusual insertion at Leu60 which forms a rigid loop that partially occludes the active site. Ecotin is an E. coli serine protease inhibitor which interacts with a usually wide range of serine proteases of varied specificity. Wild type ecotin does not bind thrombin tightly and simple modeling experiments suggest that the thrombin 60s loop stericallyl prevents ecotin from binding. The ecotin mutant M84R interacts tightly with thrombin. The structure of the ecotin-thrombin complex will reveal how ecotin adapts to the drastic steric interference of the thrombin 60s loop to bind thrombin.